Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation. Mus musculus

Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid beta (Abeta) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Abeta pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App (NL-G-F/NL-G-F) and 3xTg-AD-H mouse models. Genes commonly altered in App (NL-G-F/NL-G-F) and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App (NL-G-F/NL-G-F) cortex as Abeta amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App (NL-G-F/NL-G-F) cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Abeta amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD. Overall design: 12-months old mice from two mouse model were used in this study: AppNL-G-F/NL-G-F mice, harboring three pathogenic App-knock-in mutations that promote aggressive amyloidosis by increasing total Aβ production (Swedish mutation KM670/671NL), increasing the Aβ42/Aβ40 ratio (Iberian mutation I716F), and promoting Aβ aggregation through facilitating oligomerization and reducing proteolytic degradation (Arctic mutation E693G), under the control of the endogenous APP promoter; and 3xTg-AD-H mouse carrying two mutated human overexpressed transgenes, APP (Swedish KM670/671NL) and MAPT (P301L), driven by exogenous Thy1.2 promoter with a knock-in mutation of Psen1 (M146V), together with their correspondent controls (male, n=3 for each group). RNA samples prepared from total cortex were subjected to microarray analysis using the Affymetrix Mouse Gene 2.0 ST platform.